Delstrigo (Tablets) Instructions for Use

Marketing Authorization Holder

MSD Pharmaceuticals, LLC (Russia)

Manufactured By

MSD International, GmbH (Ireland)

Packaging and Quality Control Release

MERCK SHARP & DOHME, B.V. (Netherlands)

Or

AKRIKHIN Chemical and Pharmaceutical Plant, JSC (Russia)

ATC Code

J05AR24 (Lamivudine, tenofovir disoproxil and Doravirine)

Active Substances

Lamivudine (Rec.INN registered by WHO)

Doravirine (Rec.INN registered by WHO)

Tenofovir (Rec.INN registered by WHO)

Dosage Form

Delstrigo

Film-coated tablets, 100 mg+300 mg+245 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets yellow, oval, biconvex, engraved with the company logo (graphic symbol) and “776” on one side and smooth on the other.

Excipients: hypromellose acetate succinate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, film coating (hypromellose, titanium dioxide, lactose monohydrate, triacetin, yellow iron oxide dye), carnauba wax.

30 pcs. – high-density polyethylene bottles (1) – cardboard packs^×.

^× to control the first opening, stickers may be applied to the cardboard pack.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Combined antiviral agent for the treatment of HIV.

Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 and inhibits HIV-1 replication by non-competitively inhibiting HIV-1 reverse transcriptase (RT). Doravirine does not inhibit human cellular DNA polymerases α, β and mitochondrial DNA polymerase γ.

Lamivudine is a nucleoside analogue. Inside cells, Lamivudine is phosphorylated to the active metabolite 5′-triphosphate (Lamivudine triphosphate/3TC-TP). The main mechanism of action of 3TC-TP is inhibition of RT by DNA chain termination after the incorporation of the nucleotide analogue.

Tenofovir in the form of disoproxil fumarate is an acyclic nucleoside phosphonate analogue of adenosine monophosphate. Formation of tenofovir diphosphate requires initial hydrolysis of the tenofovir disoproxil diester to tenofovir, followed by phosphorylation by cellular enzymes. Tenofovir diphosphate inhibits HIV-1 RT activity by competing with the natural substrate deoxyadenosine 5′-triphosphate, via DNA chain termination after incorporation into DNA. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β and mitochondrial DNA polymerase γ.

Antiviral activity in cell culture

Doravirine demonstrated an EC₅₀ value of 12.0 ±4.4 nmol/L against laboratory strains of wild-type HIV-1 when tested in the presence of 100% healthy human serum using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC₅₀ values from 1.2 nmol/L to 10.0 nmol/L. The antiviral activity of doravirine was not antagonistic when co-administered with lamivudine and tenofovir disoproxil.

The antiviral activity of lamivudine against HIV-1 was assessed using several cell lines, including monocytes and peripheral blood mononuclear cells (PBMCs), by standard susceptibility assays. EC₅₀ values ranged from 0.003 to 15 µmol/L (1 µmol/L = 0.23 µg/mL). The median EC₅₀ values for lamivudine were 60 nmol/L (range 20 to 70 nmol/L), 35 nmol/L (range 30 to 40 nmol/L), 30 nmol/L (range 20 to 90 nmol/L), 20 nmol/L (range 3 to 40 nmol/L), 30 nmol/L (range 1 to 60 nM), 30 nmol/L (range 20 to 70 nmol/L), 30 nmol/L (range 3 to 70 nmol/L) and 30 nmol/L (range 20 to 90 nmol/L) against HIV-1 subtypes A-G and group O viruses (n= 3 except n = 2 for subtype B), respectively. Ribavirin (50 µmol/L), used to treat chronic hepatitis C virus infection, reduced the activity of lamivudine against HIV-1 in MT-4 cells by 3.5-fold.

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T-lymphoblastoid cell lines, primary monocytes/macrophages and peripheral blood lymphocytes. The EC₅₀ values for tenofovir ranged from 0.04 to 8.5 µmol/L. Tenofovir exhibits antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F, G and O (EC₅₀ value range 0.5 to 2.2 µmol/L).

Pharmacokinetics

Doravirine

The pharmacokinetics of doravirine were studied in healthy volunteers and HIV-1-infected patients. The pharmacokinetics of doravirine are similar in healthy volunteers and HIV-1-infected patients. Steady state was typically reached by the second day with once-daily dosing, with an accumulation ratio of 1.2 to 1.4 for AUC_0-24, C_max, and concentration at 24 hours (C₂₄). Steady-state pharmacokinetic parameters of doravirine after administration of a 100 mg dose once daily in HIV-1-infected patients based on population pharmacokinetic analysis (geometric mean value (%CV – geometric coefficient of variation): AUC_0-24 37.8 (29) µmol/L×h, C_max 2.26(19) µmol/L, C₂₄ 930 (63) nmol/L.

After oral administration, C_max in plasma is reached 2 hours after administration. The absolute bioavailability of doravirine was approximately 64% for the 100 mg tablet. Based on intravenous microdose administration, the V_d of doravirine is 60.5 L. Doravirine is approximately 76% bound to plasma proteins. Based on in vitro data, Doravirine is primarily metabolized via CYP3A.

The terminal T_1/2 of doravirine is about 15 hours. Doravirine is primarily eliminated via CYP3A-mediated oxidative metabolism. Biliary excretion of unchanged drug may contribute to the elimination of doravirine, but this route of elimination is not expected to be significant. Urinary excretion of unchanged doravirine is negligible.

Lamivudine

After oral administration, Lamivudine is rapidly absorbed and extensively distributed. After multiple doses of lamivudine 300 mg once daily for 7 days in 60 healthy volunteers, the steady-state C_max was 2.04±0.54 µg/mL (mean±SD), the steady-state AUC over 24 hours (AUC_24,ss) was 8.87±1.83 µg×hour/mL. Binding to plasma proteins is low. Approximately 71% of an intravenous dose of lamivudine is recovered as unchanged lamivudine in the urine. Metabolism is a minor route of elimination. The only known metabolites of lamivudine in humans are the trans-sulfoxide metabolites (approximately 5% of the oral dose after 12 hours). In most single-dose studies in HIV-1-infected patients or healthy volunteers, the observed mean T_1/2 from blood sampling over 24 hours post-dose ranged from 5 to 7 hours. In HIV-1-infected patients, the total clearance was 398.5±69.1 mL/min (mean±SD).

Tenofovir

After oral administration of 245 mg of tenofovir disoproxil on an empty stomach to HIV-1 infected patients, C_max was achieved at 1 hour. C_max and AUC values were 0.30±0.09 µg/mL and 2.29±0.69 µg×h/mL, respectively. The bioavailability of tenofovir from tenofovir disoproxil in fasted patients was approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro over the concentration range of 0.01 to 25 µg/mL. Approximately 70-80% of the tenofovir dose administered intravenously is recovered as unchanged substance in the urine within 72 hours of administration. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance of 243.5±33.3 mL/min (mean±SD) in adults with CrCl greater than 80 mL/min. After oral administration, the terminal T_1/2 of tenofovir is approximately 12 to 18 hours.

Indications

Treatment of HIV-1 infection in adult patients.

ICD codes

Dosage Regimen

Administer orally, once daily as a fixed-dose combination tablet.

Take the tablet with or without food.

Swallow the tablet whole; do not crush, split, or chew.

For patients switching from a stable antiretroviral regimen, initiate Delstrigo immediately after discontinuation of the previous therapy.

Do not co-administer with other antiretroviral medications, as this is a complete regimen.

Contraindicated in patients with creatinine clearance (CrCl) less than 50 mL/min.

Assess estimated CrCl before initiating therapy.

If a dose is missed by more than 12 hours, skip the missed dose and take the next dose at the regular time.

If vomiting occurs within 1 hour of taking the tablet, administer another dose.

Do not use in patients with severe hepatic impairment (Child-Pugh Class C).

Avoid concomitant use with strong cytochrome CYP3A inducers, including rifampin, carbamazepine, and St. John’s wort.

If co-administered with the moderate inducer rifabutin, an additional 100 mg dose of doravirine is required approximately 12 hours after the daily Delstrigo dose; this requires separate dosing of doravirine, not an extra Delstrigo tablet.

Adverse Reactions

Blood and lymphatic system disorders: uncommon – neutropenia, anemia, thrombocytopenia; very rare – true red cell aplasia.

Metabolism and nutrition disorders: uncommon – hypophosphatemia, hypokalemia; rare – hypomagnesemia, lactic acidosis.

Psychiatric disorders common – abnormal dreams, insomnia; uncommon – nightmares, depression, anxiety, irritability, confusion, suicidal thoughts; rare – aggression, hallucinations, adjustment disorder, mood altered, somnambulism.

Nervous system disorders common – headache, dizziness, somnolence; uncommon – attention disturbance, memory impairment, paresthesia, hypertonia, poor quality sleep; very rare – peripheral neuropathy (or paresthesia).

Cardiac disorders uncommon – hypertension.

Respiratory, thoracic and mediastinal disorders: common – cough, nasal symptoms; rare – dyspnea, tonsillar hypertrophy.

Gastrointestinal disorders common – nausea, diarrhea, abdominal pain, vomiting, flatulence; uncommon – constipation, abdominal discomfort, abdominal distension, dyspepsia, loose stools, gastrointestinal motility disorder; rare – painful defecation, fatty liver, hepatitis.

Skin and subcutaneous tissue disorders common – alopecia, rash; uncommon – pruritus; rare – allergic dermatitis, rosacea, angioedema.

Musculoskeletal and connective tissue disorders common – muscle tissue disorders; uncommon – myalgia, arthralgia, rhabdomyolysis, muscle weakness; rare – musculoskeletal pain, osteomalacia (manifesting as bone pain and rarely contributing to bone fractures), myopathy.

Renal and urinary disorders uncommon – increased creatinine, proximal renal tubulopathy (including Fanconi syndrome); rare – acute kidney injury, renal impairment, kidney stones, nephrolithiasis, acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute interstitial), nephrogenic diabetes insipidus.

General disorders and administration site conditions common – fatigue, pyrexia; uncommon – asthenia, malaise; rare – chest pain, chills, pain, thirst.

Investigations common – increased ALT; uncommon – increased AST, lipase, amylase, decreased hemoglobin; rare – increased blood creatine phosphokinase.

Contraindications

CrCl<50 mL/min; severe hepatic impairment (Child-Pugh class C); concomitant use with drugs that are strong inducers of the cytochrome CYP3A system (due to a significant decrease in plasma concentrations of doravirine), including (but not limited to) carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampicin, rifapentine, St. John’s wort preparations, mitotane, enzalutamide, lumacaftor; children under 18 years of age; pregnancy, breastfeeding period; simultaneous use with other antiretroviral drugs; hypersensitivity to doravirine, lamivudine, tenofovir.

With caution

Use with caution concomitantly with the following drugs: rifabutin, dabrafenib, lesinurad, bosentan, thioridazine, nafcillin, modafinil, telotristat ethyl, tacrolimus and sirolimus.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindicated for use in severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

Contraindicated for use in CrCl<50 mL/min.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients to avoid the risk of exacerbation of chronic diseases.

Special Precautions

Effective viral suppression with antiretroviral therapy has been proven to significantly reduce the risk of sexual transmission of HIV-1, however, residual risk cannot be excluded. Precautions should be taken to prevent virus transmission in accordance with national guidelines.

In patients co-infected with HIV-1 and HBV, severe exacerbations of hepatitis B (e.g., hepatic decompensation and liver failure) have been reported, which led to discontinuation of lamivudine or tenofovir disoproxil. In patients co-infected with HIV-1 and HBV, clinical and laboratory signs should be carefully monitored for at least several months after discontinuation of therapy with this combination. If necessary, initiation of HBV therapy may be appropriate, especially in patients with advanced liver disease or cirrhosis, as post-treatment flare can lead to hepatic decompensation and liver failure.

In HIV-infected patients with risk factors for renal dysfunction, whose condition remained stable on tenofovir disoproxil therapy, cases of acute renal failure have been reported after initiation of high doses or multiple NSAIDs. Some patients required hospitalization and renal replacement therapy. In patients at risk of renal dysfunction, alternatives to NSAID use should be considered if necessary.

Persistent or increasing bone pain, limb pain, fractures and/or muscle pain or weakness may be symptoms of proximal renal tubulopathy and require assessment of renal function in at-risk patients.
It is recommended to assess estimated CrCl in all patients prior to initiation of therapy and as clinically required during therapy with this combination. In patients at risk of renal dysfunction, including patients who have previously experienced such events during therapy with adefovir dipivoxil, it is recommended to assess estimated CrCl, serum phosphorus, urine glucose and urine protein prior to initiation of therapy with this combination; the need for more frequent monitoring of renal function during therapy with this combination should be assessed according to the patient’s medical condition. Lamivudine and tenofovir disoproxil are primarily eliminated by the kidneys.

In clinical studies in HIV-1 infected adult patients, administration of tenofovir disoproxil was associated with a significant decrease in bone mineral density (BMD) and an increase in biochemical markers of bone metabolism, indicating that it enhances bone metabolism relative to comparator drugs. Serum parathyroid hormone and 1,25-dihydroxyvitamin D concentrations were also higher in patients receiving tenofovir disoproxil. In other studies (prospective and cross-sectional), the most pronounced decrease in BMD was reported in patients receiving tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor. Bone disorders (sometimes contributing to fractures) may be associated with proximal renal tubulopathy.

The effect of tenofovir disoproxil-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk is unknown. Assessment of BMD should be considered in HIV-infected adult patients with a history of pathological bone fractures or other risk factors for osteoporosis or bone loss. Although the effect of calcium and vitamin D supplementation has not been studied, this type of supportive therapy may be beneficial for all patients. If bone disorders are anticipated, appropriate counseling should be obtained.

Cases of osteomalacia associated with proximal tubular tubulopathy, manifesting as bone pain or limb pain and contributing to fractures, have been reported in association with the use of tenofovir disoproxil. Arthralgia and muscle pain or weakness have also been reported with proximal tubular tubulopathy. Signs of hypophosphatemia and osteomalacia secondary to proximal tubular tubulopathy should be checked in patients at risk of renal impairment who experience persistent or worsening muscle and bone symptoms during therapy with drugs containing tenofovir disoproxil.

Immune reconstitution syndrome has been described in patients receiving combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients with an immune response may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP) or tuberculosis), which may require further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, although the timing of onset is variable and may occur many months after initiation of treatment.

Effect on ability to drive and operate machinery

This combination may have a minor influence on the ability to drive and use machines. Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with this combination.

Drug Interactions

This combination is a complete regimen for the combined therapy of HIV-1 infection; therefore, concomitant therapy with other antiretroviral drugs should not be administered. Any drug interaction established for each of these active substances is also applicable to this combination.

Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A affect the clearance of doravirine. Therefore, this combination is contraindicated for concomitant use with drugs that are strong inducers of CYP3A, as a significant decrease in doravirine plasma concentration is expected, which may reduce the efficacy of this combination.

Concomitant use with the moderate CYP3A inducer rifabutin decreases doravirine plasma concentration.

Concomitant use of this combination with other moderate CYP3A inducers has not been studied, but a decrease in doravirine concentration is expected.

Concomitant use of this combination and CYP3A inhibitor drugs may lead to an increase in doravirine plasma concentration. However, no dose adjustment is required when doravirine is co-administered with CYP3A inhibitors.

However, co-administration of doravirine and the sensitive CYP3A substrate midazolam leads to an 18% decrease in midazolam exposure, indicating that Doravirine may be a weak inducer of CYP3A. Thus, caution should be exercised when doravirine is co-administered with drugs that are sensitive substrates of CYP3A, which may also have a narrow therapeutic range (e.g., tacrolimus and sirolimus).

Lamivudine is eliminated primarily by the kidneys by a combination of glomerular filtration and active tubular secretion. Administration of this combination with drugs that reduce renal function or compete for active tubular secretion may lead to an increase in lamivudine serum concentration.

Tenofovir is eliminated primarily by the kidneys by a combination of glomerular filtration and active tubular secretion. Use of this combination with drugs that reduce renal function or compete for active tubular secretion via OAT1, OAT3, or MRP4 may lead to an increase in tenofovir serum concentration. Use of this combination concurrently with or recently after nephrotoxic drugs should be avoided, including (but not limited to) acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high doses of NSAIDs or multiple NSAIDs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.